Fibroblast Growth Factor Inducible 14
Fibroblast growth factor inducible 14 (Fn14, also known as TNF-like weak inducer of apoptosis receptor [Tweak-R] or TNFRSF12A), is a member of the Tumor Necrosis Factor receptor superfamily. Expression of Fn14 is up-regulated by growth factors in vitro and in vivo in response to tissue injury, regeneration, and inflammation.
As one of the names for Fn14 suggests, this protein is a receptor for the protein designated Tweak. Tweak binding to Fn14, or constitutive Fn14 overexpression, activates the NFκB signaling pathway, which is known to play an important role in immune and inflammatory processes, oncogenesis, and cancer therapy resistance. This interaction also controls many cellular activities including, proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. Tweak and Fn14 are also involved in tissue repair and regulation of immune functions and tumor growth. Accordingly, Fn14-mediated signaling is involved in pathways that play important roles in human diseases. Fn14-mediated signaling has been suggested to play a role in numerous diseases, including, cancer, metastasis, immunological disorders (including autoimmune diseases, graft rejection and graft versus host disease, and chronic and acute neurological conditions [including stroke]).
Fn14 is expressed by many non-lymphoid cell types (epithelial, mesenchymal, endothelial cells and neurons), by many tissue progenitor cells, including all progenitor cells of the mesenchymal lineage. This protein is highly inducible by growth factors e.g., in serum that are encountered in vivo at sites of tissue injuries and/or tissue remodeling. As a consequence Fn14 expression is relatively low in most healthy tissues, but increased in injured and/or diseased tissues.
Based on the foregoing description, the skilled artisan will be aware that compounds that bind to Fn14 are desirable. These compounds can be used to treat, prevent, diagnose or prognose Fn14-mediated conditions. In addition, it is desirable to identify and further understand the role of Fn14 in various biological conditions and diseases. In particular, the role of Fn14 in wasting disorders has not been previously demonstrated.
Wasting Disorders
Wasting disorders are a class of disorders that are characterized by progressive loss of one or more tissues, e.g., muscle and/or fat. Wasting disorders can be classified into two types: (i) those in which the tissue that is lost is the site of the disorder (e.g., muscular dystrophy); and (ii) wasting disorders that are associated with or caused by other conditions. This latter type can be associated with a variety of conditions including motor neuron disease, denervation, and ageing. Wasting disorders associated with other disorders also includes a subclass of wasting disorders known as cachexia.
Cachexia is a metabolic disorder associated with underlying illness (i.e., a condition) and characterized by loss of body weight and loss of muscle with or without loss of fat mass. Cachexia is generally associated with increased protein catabolism due to underlying disease(s). Contributory factors to the onset of cachexia are anorexia and metabolic alterations (e.g., increased inflammatory status, increased muscle proteolysis and impaired carbohydrate, protein and lipid metabolism). Conditions associated with cachexia include, but are not limited to, cancer, certain infectious diseases (e.g. tuberculosis, AIDS), some autoimmune disorders (including diabetic neuropathic cachexia, and rheumatoid cachexia), or addiction to drugs such as amphetamines or cocaine, chronic alcoholism and cirrhosis of the liver. Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia, and response to standard treatment is usually poor. Cachexia is regularly seen associated with cancer, and in that context is called “cancer cachexia”. There are also a cachectic syndromes observed in patients suffering from disorders, such as, but not limited to renal disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes and some severe cases of schizophrenia can present this disorder where it is named vesanic cachexia.
A common form of cachexia is associated with cancer. In this regard, cachexia is one of the most common manifestations of cancer and is present in up to 80% of patients with advanced cancer, including, but not limited to cancers of the breast, lung, colon, prostate, pancreas and gastrointestinal tract. Cachexia is also present early in progression of cancer with, for example, 85% of patients with gastrointestinal cancers, 83% of patients with pancreatic cancer and 60% of patients with lung cancer presenting with cachexia upon diagnosis. Cachexia accounts for >20% of all cancer-related deaths and is associated with reduced mobility, increased risk of complications in surgery, impaired response to chemo-/radio-therapy, decreased survival time and increased psychological distress, leading to an overall reduction in quality of life for sufferers. Currently, the only definitive treatment of cancer cachexia is removal of the causative tumor. Short of achieving this goal, which is often compromised by the patients' inability to tolerate cancer treatments due to their cachexia, various measures have been undertaken to ameliorate cachexia, however with limited success. Various agents have been administered in attempts to retard or halt progressive cachexia in cancer patients. These agents include orexigenic agents (appetite stimulants), corticosteroids, cannabinoids, serotonin antagonists, prokinetic agents, androgens and anabolic agents, anticytokine agents, non-steroidal anti-inflammatory drugs, and regulators of circadian rhythm.
It will be apparent to the skilled artisan from the foregoing that the identification of improved Fn14-binding proteins for medical and diagnostic treatment would be useful. Furthermore, the treatment of wasting disorders, such as cachexia, is a significant unmet medical need. Thus, there is a need in the art for therapies that can ameliorate, delay or prevent wasting disorders, including, unintended body weight loss, cachexia, muscle and/or fat wasting, weakness and/or fatigue associated with one or more disorders. Desirably, such therapies reduce mortality and/or enhance and/or prolong patients' quality of life, which can assist with therapeutic and/or prophylactic methods, e.g., to treat a condition causing or associated with the wasting disorder.